Arthritis Res Ther. 2013 Jul 22;15(4):R75. doi: 10.1186/ar4252.

Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of rheumatoid arthritis.

Tsunemi S, Iwasaki T, Kitano S, Matsumoto K, Takagi-Kimura M, Kubo S, Tamaoki T, Sano H.



INTRODUCTION: Hepatocyte growth factor (HGF) is a potent proangiogenic molecule that induces neovascularization. The HGF antagonist, NK4, competitively antagonizes HGF binding to its receptor. In the present study, we determined the inhibitory effect of NK4 in a rheumatoid arthritis (RA) model using SKG mice.

METHODS: Arthritis was induced in SKG mice by a single intraperitoneal injection of β-glucan. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was also injected intravenously at the time of or 1 month after β-glucan injection. Ankle bone destruction was examined radiographically. The histopathologic features of joints were examined using hematoxylin and eosin and immunohistochemical staining. Enzyme-linked immunosorbent assays were used to determine the serum levels of HGF, interferon γ (IFN-γ, interleukin 4 (IL-4) and IL-17 production by CD4⁺ T cells stimulated with allogeneic spleen cells.

RESULTS: The intravenous injection of AdCMV.NK4 into SKG mice suppressed the progression of β-glucan-induced arthritis. Bone destruction was also inhibited by NK4 treatment. The histopathologic findings of the ankles revealed that angiogenesis, inflammatory cytokines and RANKL expression in synovial tissues were significantly inhibited by NK4 treatment. Recombinant NK4 (rNK4) proteins inhibited IFN-γ, IL-4 and IL-17 production by CD4⁺ T cells stimulated with allogeneic spleen cells.

CONCLUSIONS: These results indicate that NK4 inhibits arthritis by inhibition of angiogenesis and inflammatory cytokine production by CD4⁺ T cells. Therefore, molecular targeting of angiogenic inducers by NK4 can potentially be used as a novel therapeutic approach for the treatment of RA.

PMID: 23876175




Figure 1

Rheumatoid arthritis (RA), a chronic inflammatory disease, is characterised by the proliferation of synovial cells, a process that ultimately leads to the destruction of the underlying cartilage and bone. Such synovial expansion is dependent on an adequate blood supply, and angiogenesis has been implicated in the development of RA. Inhibiting the development of new blood vessels could therefore prove effective in blocking disease progression. Hepatocyte growth factor (HGF) is known to be a potent angiogenic factor that stimulates endothelial cell growth. Studies have already shown that inhibiting HGF signaling may help prevent tumor metastasis. We investigated whether HGF inhibition may be similarly beneficial in preventing disease progression in a mouse model of RA, as reported in Arthritis Research & Therapy 2013. Using an adenovirus expressing the gene for the HGF antagonist NK4 (AdCMV.NK4), we assessed the effects of blocking HGF on joint swelling and histopathologic changes in β-glucan induced arthritis in SKG mice – an established genetic model for RA. An adenovirus carrying the LacZ gene (AdCMV.LacZ) was used as the control. To assess the preventive and therapeutic effects of the treatment, AdCMV.NK4 and the control were administered intravenously at the time of β-glucan injection and 1 month after the injection, respectively. In both experiments mice that received AdCMV.NK4 had less joint swelling (as determined by the clinical score and ankle volume) 60 days after β-glucan injection compared with those that received the control. The results of the x-ray examinations of the ankle joints supported these findings (Figure 1).


In recent study, we investigated the role of c-Met signaling in osteoblast differentiation using C2C12 myoblasts, a cell line derived from murine satellite cells (FEBS Open Bio 2015). We found that although the c-Met-MEK-ERK-Smad and c-Met-PI3K-AKT-Smad signaling pathways positively regulate osteoblast differentiation, c-Met signaling negatively regulates osteoblast differentiation, independent of the MEK-ERK-Smad and PI3K-AKT-Smad pathways (Figure 2). Therefore, blocking c-Met signaling might serve as a therapeutic strategy not only for blocking synovial cell proliferation but also to repair destructed bone in patients with RA.


Figure 2



Tsuyoshi Iwasaki, M.D., PhD

Division of Pharmacotherapy, Department of Pharmacy, School of Pharmacy,

Hyogo University of Health Sciences,

1-3-6 Minatojima, Chuo-ku, Kobe, 650-8530, Japan

Telephone number: 81-78-304-3138

Fax number: 81-78-304-2838

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